Contribution of Gigantocellular neurons of the medullar reticular formation to awakening from a low brain activity state

髓质网状结构的巨细胞神经元对从低脑活动状态唤醒的贡献

• 批准号: 9405052
• 负责人: Diany Paola Calderon
• 金额: $ 37.75万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405052
• 关键词: Adrenergic Agents; Anesthesia procedures; Animals; Anterior; Anterior Hypothalamus; Area; Arousal; Basic Science; Behavior; Bilateral; Brain; Brain Injuries; Brain Stem; Cell Nucleus; Cells; Cervical; Coma; Complement; Conscious; Data; Deep Brain Stimulation; Disinhibition; Dorsal; Elements; FOS gene; Fire - disasters; Functional Magnetic Resonance Imaging; Glutamates; Goals; Hypothalamic structure; Imaging technology; Impairment; Intralaminar Nuclear Group; Label; Light; Location; Methodology; Midbrain structure; Motor; Neurons; Parvalbumins; Pathologic; Pathway interactions; Patients; Pharmacology; Pontine structure; Population; Posterior Hypothalamus; Recovery; Reticular Formation; Role; Sensory; Site; Sleep; Stimulus; Structure; System; Testing; Thalamic structure; Unconscious State; Ventral Tegmental Area; Wakefulness; Weather; awake; basal forebrain; cholinergic neuron; diencephalon; dorsal raphe nucleus; extracellular; improved; in vivo; innovative technologies; locus ceruleus structure; midbrain central gray substance; neuronal circuitry; neuroregulation; new technology; noradrenergic; novel; novel strategies; optogenetics; parabrachial nucleus; prevent; public health relevance; recruit; relating to nervous system; response

 DESCRIPTION (provided by applicant): Neuromodulation is a promising novel methodology deployed to improve the conditions of thousands of patients whose consciousness is impaired after brain injury. Attempts at neuromodulation using deep brain stimulation (DBS) have targeted a number of loci in the brain arousal pathways such as the thalamus, mesencephalon and cervical cord. However, recovery following single location stimulation remains modest, especially in comatose patients. Although some of these pathways can trigger awakening from sleep or light planes of anesthesia upon activation are insufficient to promote arousal from a deeper arousal state like coma. Furthermore, selective damage to one of these regions, even bilateral, rarely results in permanent unconsciousness. Interpretation of these results suggests that arousal pathways are redundant however, they are not functionally interchangeable. While this implies that the full complement of arousal from a deep arousal state requires coordination of multiple pathways, the mechanism through which this coordination is achieved by the brain is poorly understood. We aim to overcome this challenge uncovering novel neuronal circuits that promote wakefulness through basic research. Considering that medullary reticular neurons project to arousal- modulating areas throughout the brain, integrate a broad range of sensory and autonomic inputs, and fire in response to salient stimuli in close association with the initiation of behaviors, we modulated their activity during a pharmacologic induced coma (PIC). Our results showed that activation of an area located at the anterior border of the nucleus gigantocellularis (aNGC)- elicited robust cortical, autonomic and motor arousal during a state of PIC. To understand how this small subpopulation of neurons exerts such widespread activational effects on arousal, we analyzed immunolabeling of c-Fos-a well-established marker of neuronal activation-following pharmacologic activation of aNGC neurons. C-Fos labeling was sparse and largely limited to structures known to participate in arousal including rhombenchephalon (locus coeruleus and parabrachial nucleus); mesencephalon (periaqueductal gray and ventral tegmental area); diencephalon (intralaminar thalamic nuclei as well as posterior and anterior hypothalamus); and basal forebrain. These findings suggest that aNGC is able to recruit these pathways to trigger arousal from a dense PIC. This proposal characterizes aNGC as a new site to promote arousal from a coma-like state and proposes recruitment of multiple arousal pathways through aNGC as new mechanism to produce widespread activational state resulting in wakefulness. Using extracellular in vivo recordings and innovative technology like optogenetic functional magnetic resonance imaging (ofMRI) we will dissect the circuitry involved in aNGC- stimulated arousal and we will visualize the dynamics of multi-area activation. Results of this study will uncover novel mechanisms leading to new approaches for emerging treatments for patients under coma state.

 描述（由申请人提供）：神经调节是一种很有前途的新方法，用于改善脑损伤后意识受损的数千名患者的状况。使用深部脑刺激（DBS）进行神经调节的尝试已经靶向脑唤醒通路中的许多位点，例如丘脑、中脑和颈髓。然而，单部位刺激后的恢复仍然有限，特别是在昏迷患者中。虽然这些通路中的一些可以触发从睡眠或轻度麻醉中醒来，但激活后的麻醉平面不足以促进从更深的唤醒状态（如昏迷）中唤醒。此外，对其中一个区域的选择性损害，即使是双侧的，也很少导致永久性无意识。这些结果的解释表明，唤醒途径是多余的，但它们在功能上是不可互换的。虽然这意味着从深度唤醒状态中唤醒的完整补充需要多种途径的协调，但大脑实现这种协调的机制却知之甚少。我们的目标是克服这一挑战，通过基础研究发现新的神经元回路，促进觉醒。考虑到延髓网状神经元投射到整个大脑的唤醒调节区域，整合广泛的感觉和自主输入，并响应于与行为启动密切相关的显著刺激而放电，我们在药物诱导昏迷（PIC）期间调节它们的活性。我们的研究结果表明，激活的区域位于前边缘的神经细胞核（aNGC）-引起强大的皮质，自主神经和运动唤醒在PIC的状态。为了了解这个小的神经元亚群如何对觉醒产生如此广泛的激活作用，我们分析了c-Fos的免疫标记-一种公认的神经元激活的标记物-在aNGC神经元的药理学激活之后。C-Fos标记是稀疏的，主要限于已知参与觉醒的结构，包括菱脑（蓝斑和臂旁核）;中脑（导水管周围灰质和腹侧被盖区）;间脑（丘脑板内核以及下丘脑后部和前部）;和基底前脑。这些发现表明，aNGC能够招募这些通路，以触发从密集的PIC唤醒。该提议将aNGC表征为促进从昏迷样状态唤醒的新位点，并提出通过aNGC招募多个唤醒通路作为产生导致觉醒的广泛激活状态的新机制。使用细胞外体内记录和创新技术，如光遗传学功能磁共振成像（ofMRI），我们将解剖参与aNGC刺激唤醒的电路，我们将可视化多区域激活的动态。这项研究的结果将揭示新的机制，导致昏迷状态下的患者的新兴治疗的新方法。